Download Intravitreal bevacizumab: safety of multiple doses from a

O R I G I N A L
A R T I C L E
Danny S Ng
Alvin KH Kwok
Clement W Chan
Walton WT Li
吳兆駿
郭坤豪
陳偉能
李維達
Intravitreal bevacizumab: safety of multiple doses
from a single vial for consecutive patients
Objectives To report the incidence of endophthalmitis after intravitreal
injection of anti–vascular endothelial growth factor and the
safety profile of multiple doses of bevacizumab from the same
vial reused for multiple patients.
Design Case series.
Setting A private hospital in Hong Kong.
Patients A systematic retrospective review of consecutive intravitreal
anti–vascular endothelial growth factor injections between
5 June 2006 and 17 December 2010 at a single institute was
conducted. Patients were identified from prospectively designed
audit forms, and each patient’s medical record was reviewed for
any documented complications. Bevacizumab 1.25 mg/0.05 mL
to 2.50 mg/0.1 mL was aspirated from the designated vial, with a
maximum of 10 consecutive injections being aspirated from the
same vial. The opened vial was then discarded without overnight
storage. Ranibizumab was aspirated from the commercially
available 1 mg/0.1 mL single-use vial.
Results A total of 1655 intravitreal anti–vascular endothelial growth
factor injections into 392 eyes of 383 patients were evaluated
during the study period. There were 1184 bevacizumab
injections and 471 ranibizumab injections. There was one case of
suspected endophthalmitis after ranibizumab injection, though
culture of the vitreous tap was negative. The point prevalence
of endophthalmitis was 0.06% (1/1655) for the total number
of injections: 0.21% (1/471) after ranibizumab, and 0% after
bevacizumab.
Conclusion Although many centres aliquot multiple syringes from a single
vial to be kept in a refrigerator for use, the current study shows
that so long as proper sterile techniques are implemented, there
were no cases of endophthalmitis from using the same vial,
which was reused for a maximum of 10 consecutive injections.
For intravitreal injection, bevacizumab costs approximately
US$50 to US$100 per dose, as opposed to US$2000 per dose
for ranibizumab. Sharing multiple doses of bevacizumab from a
single vial can substantially reduce the cost of treatment.
Key words
Endophthalmitis; Intravitreal Injections;
Ranibizumab; Receptors, Vascular
endothelial growth factor; Bevacizumab
Hong Kong Med J 2012;18:488-95
Department of Ophthalmology, Tung
Wah Eastern Hospital, Sheung Wan,
Hong Kong
DS Ng, MRCSEd
CW Chan, FRCS
Department of Ophthalmology, Hong
Kong Sanatorium and Hospital,
Happy Valley, Hong Kong
AKH Kwok, MD, FRCS
WWT Li, MD, FRCS
New knowledge added by this study
• The frequency of endophthalmitis was 0.06% (1/1655) for the total number of injections, being
0.21% (1/471) after ranibizumab and 0% after bevacizumab.
• Using the same vial of bevacizumab for a maximum of 10 consecutive injections was safe
when proper sterile techniques are implemented.
Implications for clinical practice or policy
• Bevacizumab is a safe alternative to ranibizumab.
• In a clinic setting, injections of bevacizumab can be safely used from the same vial for up to
10 consecutive injections.
Introduction
Anti–vascular endothelial growth factor (anti-VEGF) therapy plays an important role in many
ocular diseases, particularly posterior segment pathologies characterised by choroidal
Correspondence to: Dr AKH Kwok neovascularisation (CNV) and macular oedema. While only ranibizumab (Lucentis;
Email: [email protected] Genetech, San Francisco [CA], US) and pegaptanib (Macugen; Eyetech Pharmaceuticals,
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# Safety of intravitreal bevacizumab injections #
New York, US) are labelled for intravitreal use,
bevacizumab (Avastin; Genetech, San Francisco
[CA], US) is currently also being used ‘off-label’ for
the treatment of ocular diseases. Bevacizumab was
approved by the US Food and Drug Administration
(FDA) for treating patients with metastatic colorectal
cancer in February 2004.1 Promising results were
first reported using systemic bevacizumab in a case
series of nine patients with age-related macular
degeneration (AMD),2 followed by intravitreal
injection of a smaller dose which also resulted in
anatomical and functional improvements without
significant toxicity.3-5 Recently, the Comparison of
Age-Related Macular Degeneration Treatments
Trials (CATT)—a large, prospective, multicentre,
randomised controlled trial—concluded that
monthly intravitreal injections of either anti-VEGF
drug resulted in the same visual acuity outcomes at
1 year.6 Furthermore, the outcomes of the as-needed
regimen with bevacizumab appeared similar to those
of ranibizumab therapy. The data from the CATT
study supported the use of bevacizumab, and the
as-needed regimen appeared to be an acceptable
alternative to the monthly regimen.
Commercially available bevacizumab comes in
preservative-free 100 mg/4 mL vials, and is intended
for use at relatively high concentrations on a single
colon cancer patient. In this era of tremendous
emphasis on health care cost containment in
both developed and developing countries, it is a
common practice among hospitals, clinics, and
compounding pharmacies to divide the large volume
of bevacizumab into smaller units that are suitable
for single-use intravitreal doses for individual eyes.
Endophthalmitis, although a rare complication
of intravitreal injection with anti-VEGF agents, is
a serious concern due to its devastating visual
consequence and the increasing frequency of
intravitreal injections being given worldwide.
Scientific data and guidelines have been published
on the necessary risk management procedures
pre-injection, peri-injection, and post-injection.7-9
Nevertheless, there have been concerns about
potential contamination associated with dividing the
large volumes contained in vials of bevacizumab into
smaller units. Though these misgivings have not been
substantiated, a number of large series reporting
complications after intravitreal bevacizumab did not
provide information regarding how intravitreal doses
of bevacizumab were prepared.10-15 Currently, there is
no consensus within the ophthalmic community on
whether compounding the large bevacizumab vial
into several aliquots or reusing the same original vial
for consecutive injections could minimise the risk
of endophthalmitis.16-21 We report the safety profile
of withdrawing multiple doses of bevacizumab
from the original 4 mL vial and its reuse for multiple
consecutive patients in an office setting.
玻璃體內bevacizumab注射治療：
單瓶分用的安全性
目的 報告進行玻璃體內抗血管生長因子注射後出現眼內炎
的發生率，以及單瓶分用bevacizumab的安全性。
設計 病例系列。
安排 香港一所私家醫院。
患者 2006年6月5日至2010年12月17日期間接受玻璃體內
抗血管生長因子注射的病人。根據前瞻性設計審查
表把有關病人納入研究範圍，並翻查每位病人的病歷
紀錄。從一瓶bevacizumab吸出介乎1.25 mg/0.05 mL
至2.50 mg/0.1 mL的劑量，每瓶最多十次。已開啟的
藥瓶會被丟棄，不會隔夜儲存。另使用市售劑量為
1 mg/0.1 mL的ranibizumab。
結果 研究期間共為383名病人（392例）進行1655次玻璃
體內抗血管生長因子注射，包括1184次bevacizumab
注射和471次ranibizumab注射。發現一個懷疑因
ranibizumab注射後感染眼內炎的病例，但其玻璃
體液微生物培養呈陰性。眼內炎的時點患病率為
0.06%（1/1655）：ranibizumab為0.21%（1/471），
bevacizumab則為0%。
結論 很多中心會單瓶分用並把分用的注射器存放在冰箱
中。本研究結果顯示只要進行正確的消毒程序，即
使單瓶分用（每瓶可連續進行最多十次的注射），
亦無眼內炎的感染病例。玻璃體注射的費用方面，
每次bevacizumab注射需美金50至100元不等，而
每次ranibizumab注射則需美金2000元。單瓶分用
bevacizumab可大大減低治療成本。
Methods
This study was performed in accordance with
the standards of the Declaration of Helsinki and
approved by the Institutional Review Board of
the Hong Kong Sanatorium and Hospital. Patients
were informed about the off-label conditions of
intravitreal bevacizumab. Women of childbearing
age were also informed about the possible risks to
the fetus and avoiding conception was advised for 3
months after injection. At each post-injection visit,
patients were monitored for ocular side-effects (bestcorrected visual acuity, intra-ocular pressure [IOP],
indirect ophthalmoscopy, slit-lamp biomicroscopy)
and systemic effects/adverse effects (medication
changes, high blood pressure, clinical features of a
cerebrovascular accident, myocardial infarction, or
ischaemia).
Since 5 June 2006, a prospectively designed
audit was carried out on every patient receiving an
anti-VEGF injection (ranibizumab and bevacizumab)
in the injection room of the out-patient clinic at the
Hong Kong Sanatorium and Hospital. Each patient’s
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489
# Ng et al #
TABLE 1. Demographic characteristics of patients receiving intravitreal anti–vascular
endothelial growth factor injections
Baseline characteristic
No. of patients
Total
Ranibizumab
Bevacizumab
68 ± 16
61 ± 17
64 ± 18
Male
39
158
197
Female
23
163
186
29
122
151
Diabetes mellitus
7
79
86
Ischaemic heart disease
8
18
26
Age (years)*
Sex
Systemic hypertension
Cerebrovascular accident
1
3
4
12
30
42
Smokers
8
20
28
Glaucoma
8
55
63
Taking aspirin
* Mean ± standard deviation is shown
doctor had to fill out and file the corresponding
form. In another logbook, the date, patient name,
and doctor’s name pertaining to every injection
were recorded. All such cases from 5 June 2006 to
17 December 2010 were included, and could be
identified from the audit forms and medical records of
the respective patients. The demographics retrieved
included past health, indications for the injections,
dates and total number of injections, as well as ocular
and systemic complications related to intravitreal
anti-VEGF injections. Exclusion criteria were
intravitreal injections of non–anti-VEGF medications
(eg steroids and antibiotics), concomitant surgical
procedures (eg phacoemulsification and vitrectomy),
and injections of anti-VEGF administered outside the
injection room (eg operating theatre).
available 1 mg/0.1 mL single-use vials using the same
procedure as described for bevacizumab.
Then
5%
povidine-iodine
and
0.5%
proparacaine drops were instilled into the
conjunctiva and 10% povidone-iodine was used to
clean the eyelid skin and lashes. A sterile wire lid
speculum was inserted and lashes directed away
from the eye. The surgeon replaced the original 25gauge needle with a sterile 30-gauge needle before
intravitreal injection at 3.5 to 4 mm post-limbus,
followed by application of one drop of moxifloxacin
(Vigamox; Alcon Laboratories Inc, Fort Worth [TX],
US). Thereafter, prophylactic topical moxifloxacin
drops were applied for a few days to 1 week.
Results
A total of 1655 intravitreal anti-VEGF injections in 392
eyes of 383 patients were evaluated during the study
period. There were 1184 intravitreal injections of 1.25
mg to 2.50 mg of bevacizumab, and 471 intravitreal
injections of 0.5 mg ranibizumab. The average
number of injections per eye was 4 (range, 1-31) per
patient. Relevant demographic characteristics are
summarised in Table 1. The most common indications
for intravitreal anti-VEGF were CNV from AMD,
followed by CNV from pathological myopia (Table 2).
Analysis of all injections documented only one
instance of a clinically suspected endophthalmitis
after an injection with ranibizumab and presented
within 4 days of the procedure; subsequent
vitreous tap and culture were negative. The ocular
complications in this series are listed in Table 3. Thus,
the frequency of suspected endophthalmitis was
0.06% (1/1655) for the total number of injections; 0.21%
(1/471) after ranibizumab, and 0% after bevacizumab.
There was also one case of rhegmatogenous
retinal detachment, which presented 1 month after
All of the intravitreal injections and drug
ranibizumab injection for CNV due to pathological
preparations were carried out using a standard
myopia.
protocol. All personnel present in the injection room
wore a surgical cape and mask. In addition, doctors
washed hands and wore sterile gloves. Cleaning and Case report
sanitising of the injection room was carried out at The patient was an 80-year-old man who had
regular intervals.
suspected left ocular ischaemic syndrome with a
In the injection room, bevacizumab 1.25 mg/
0.05 mL to 2.50 mg/0.1 mL was aspirated from the
original 4 mL vial of bevacizumab with a 25-gauge
needle into a 1 mL syringe, just before the intravitreal
injection. The surface of the rubber septum of
the vial was wiped with 100% alcohol just before
insertion of the needle. The same vial was used for
10 consecutive injections and discarded. The vial was
always kept in a closed box before usage and the box
was not removed from the injection room. Opened
vials were discarded at the end of the day without
overnight storage, regardless of the residual volume.
Ranibizumab was aspirated from commercially
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history of recurrent corneal erosions, chronic eye
pain, and recurrent vitreous haemorrhage. He had
a history of combined phacoemulsification, intraocular lens implantation, pars plana vitrectomy and
had also undergone endolaser treatment 6 months
earlier. On examination, his left eye visual acuity
was hand movement and the IOP was 29 mm Hg.
Neovascularisation over the iris and an open angle
was noted. After thorough discussion of various
options, he decided to receive a 0.5 mg ranibizumab
intravitreal injection. Four days later he presented
with mild left eye redness. Upon examination, his
visual acuity remained at hand movement and the
# Safety of intravitreal bevacizumab injections #
TABLE 2. Indications for intravitreal anti–vascular endothelial growth factor injections
Indications*
No. of eyes
Ranibizumab
No. of injections
Bevacizumab
Total
Ranibizumab
Bevacizumab
Total
CNV (AMD)
29
89
118
303
322
625
CNV (pathological myopia)
11
80
91
66
333
399
DME
5
49
54
14
114
128
PCV
12
22
34
49
62
111
4
21
25
29
154
183
CRVO
BRVO
2
28
30
8
117
125
Pseudophakic CME
0
8
8
0
11
11
Idiopathic CNV
0
7
7
0
25
25
NVG
2
4
6
2
4
6
Vitreous haemorrhage (DMR)
0
6
6
0
13
13
Other secondary CNV
0
5
5
0
18
18
Chronic CSC
0
4
4
0
5
5
Uveitis CME
Total
0
4
4
0
6
6
65
327
392
471
1184
1655
* CNV denotes choroidal neovascularisation, AMD age-related macular degeneration, DME diabetic macular oedema, PCV polypoidal
choroidal vasculopathy, CRVO central retinal vein occlusion, BRVO branch retinal vein occlusion, CME cystoid macular oedema, NVG
neovascular glaucoma, DMR diabetic retinopathy, and CSC central serous chorioretinopathy
TABLE 3. Ocular complications after intravitreal anti–vascular
endothelial growth factor injections
from 0.01% to 1.6%.10-12,14-17,19,20,22 In a meta-analysis
of 105 531 injections from all major US-based
studies from 2005 to 2010, McCannel23 reported an
Type of complications
No. of cases
endophthalmitis frequency of 0.049% (approximately
Subconjunctival haemorrhage
61
1 of 1949 injections). There is a definite, albeit
Corneal injury
1
small, risk of developing endophthalmitis following
Rhegmatogenous retinal detachment
1
an intravitreous injection. During the study
Suspected endophthalmitis
1
period lasting almost 4.5 years, the frequency of
endophthalmitis we encountered after intravitreal
anti-VEGF injections was 0.06%, which is within
IOP was 18 mm Hg. Slit lamp examination showed a previously published ranges.
1 mm hypopyon, anterior chamber cells 3+, but less
Our single case of suspected endophthalmitis
neovascularisation over the iris. Dilated fundoscopy
after intravitreal ranibizumab was negative for
revealed a mild vitreous haze with a flat retina.
bacteria and fungi when assessed by microscopy and
Infective endophthalmitis was suspected. Aqueous
cultures. Sterile endophthalmitis has been reported
and vitreous taps for microscopy and culture were
after intravitreal anti-VEGF; endotoxin introduced
performed. The specimens were directly inoculated
through the injection site has been proposed as
onto various culture media and slide plates, and
a cause of severe intra-ocular inflammation.18,24
immediately sent to the microbiological laboratory.
However, such acute intra-ocular inflammation
Intravitreal amikacin (0.4 mg in 0.1 mL) and
was found to present early (within 1 day) postvancomycin (1 mg in 0.1 mL) was given. Over 1 week
injection.24 By contrast our patient presented 4 days
the hypopyon gradually disappeared and there was
after the injection, which is more typical of bacterial
clinical resolution of the endophthalmitis. The patient
endophthalmitis.14 Thus, we could not exclude the
had persistent neovascular glaucoma with an IOP of
possibility of very small microorganism load that was
40 mm Hg. His left eye vision was reduced to light
not detected in the vitreous tap sent to our laboratory.
perception and he declined further interventions.
We did not encounter endophthalmitis
Aqueous and vitreous taps for microscopy and after intravitreal bevacizumab. Hence, based on
culture were all negative.
our series, reusing the same bevacizumab vial
for multiple injections seems not to increase its
Discussion
frequency in comparison to single-use ranibizumab
The frequency of endophthalmitis after intravitreal vials. To date, other large series found no difference
anti-VEGF reported in the scientific literature varies in the endophthalmitis risk in patients receiving
Hong Kong Med J Vol 18 No 6 # December 2012 # www.hkmj.org
491
# Ng et al #
bevacizumab as opposed to ranibizumab.6,13-15,19,22 The
recent CATT study revealed no statistically significant
difference between the endophthalmitis rates after
bevacizumab and ranibizumab; the respective rates
being 2/5449 (0.04%) injections in 599 patients, and
4/5508 (0.07%) injections in 586 patients.6 Nonetheless,
the CATT study had limited statistical power to detect
important adverse events and could not definitively
conclude that both drugs had similar rates of postinjection endophthalmitis.
intravitreal bevacizumab is fairly low, the two recently
reported cases of S marcescens endophthalmitis had
devastating visual consequence and destruction of
the eye despite surgical treatment.16 To minimise
the risk of contamination, a recommendation was
made to compound drugs in an accredited pharmacy
adhering to professional standards such as those
espoused by the FDA,28 American Society of Health
System Pharmacists,29 and US Pharmacopeia (USP
chapter 79730).
Due to the lack of evidence on any increased
risk of endophthalmitis associated with preparing
bevacizumab in small doses for intravitreal use,
there is no current consensus on the optimal
protocol to minimise the risk of contamination
during the handling of this drug. Artunay et al25
reported three eyes (of 3022 injections, 0.066%) with
endophthalmitis after intravitreal bevacizumab, in
which multiple doses had been withdrawn from a
single vial in an out-patient setting. Other studies
have reported endophthalmitis, possibly related to
contamination during the compounding procedures
of bevacizumab. Yamashiro et al18 reported 14
out of 19 consecutive cases of culture-negative
endophthalmitis after intravitreal injection from
a single batch of bevacizumab. Lee et al16 reported
two patients who received intravitreal bevacizumab
on the same day that developed Serratia marcescens
endophthalmitis. Subsequent molecular typing
confirmed that the strains were identical, suggesting
contamination during compounding. However,
they did not find any case of endophthalmitis in
another group of patients that received intravitreal
bevacizumab aspirated from the same vial that was
reused for multiple consecutive injections just
before each procedure and discarded on the same
day. Similarly, the Pan-American Collaborative Retina
Study Group (PACORES) reported more frequent
endophthalmitis (6/1833 injections, 0.33%) in eyes
injected using previously compounded aliquots
than in eyes given injections from the same multidose vial (1/2470 injections, 0.04%) that was reused
appropriately.17 Contrary to the perceived higher risk
of contamination from re-utilisation of a single vial, a
higher frequency of endophthalmitis was reported in
studies utilising compounded aliquots.
According to the USP (chapter 797), the
preparation of multiple doses of bevacizumab
for intravitreal injection can be categorised as a
medium-risk compounded sterile preparation, and
the quality assurance procedures recommended
for compounding included adequate personnel
garb for sterile preparation within a laminar-airflow
workbench, routine disinfection, air quality testing
to maintain an International Organization for
Standardization (ISO) Class 5 (3520 particles/m3)
environment, and annual media-fill tests of aseptic
manipulations of every pharmacy staff member
involved in compounding.31
In 2001, there was an outbreak of 11 S marcescens
infections, including meningitis, epidural abscesses,
and septic arthritis following epidural or joint
injections of betamethasone that was compounded
at a single pharmacy.26 An investigation of the
pharmacy revealed cross-contamination of the clean
room environment and stock solutions, as well as
inadequate autoclaving temperatures, lack of terminal
sterilisation, insufficient training of pharmacy staff,
and absence of end-product sterility tests, all of
which could have contributed to the outbreak.27
Whilst the frequency of endophthalmitis after
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Drawing multiple doses from the same vial
immediately before injection has the potential for
contamination. Increasing the number of punctures
also increases the risk of contamination. This could
be due to the rubber septum increasingly wiped
by fingers or a dirty gauze, rubber stopper leakage,
poor aseptic technique (eg entering the vial without
alcohol swabbing), injection of air into the vial before
removal of the solution, a contaminated needle or
syringe used to draw medication, and inappropriate
storage durations and temperatures.32-34 Similar to
the protocol of intravitreal injection of bevacizumab
devised by Artunay et al,25 our protocol had a limit
of 10 punctures for each opened vial, as studies
have found that contamination was rare (<1 colony
forming unit/1000 perforations) when multidose vials
were punctured up to 10 times in hospital use.25,34,35
Clinicians from other specialties had longer
experience in administering multidose injections
retrieved from a single vial. Examples in the
literature include subcutaneous injections for the
immunotherapy for allergy,36 intravenous injections
of contrast media in radiology37 and anaesthetic
medications for non-emergency procedures.38 The
safety of these injections were also ensured by
hand washing, proper personnel garb, and using
sterile equipment during drug transfer, disinfection
of the rubber diaphragm with ≥70% alcohol or 10%
povidine-iodine, using sterile needles and syringes
each time a vial is entered, and avoiding touching the
needle and rubber diaphragm. Furthermore, wearing
surgical masks during withdrawal of medications
from the vial and peri-injection procedures in the
injection room may have prevented respirationassociated bacterial contamination by species such
# Safety of intravitreal bevacizumab injections #
TABLE 4. Summary of studies and reported frequencies of suspected endophthalmitis related to the preparation of bevacizumab in smaller units before
intravitreal injection
Study
Shared original vial
No. of
No. of
injections endophthalmitis
(incidence)
Wu et al (PACORES)17
2470
1 (0.04%)
Lee et al16
1420
0
3022
3 (0.066%)
Artunay et al
25
Compounded vials
Isolated organism
1 Coagulase -ve
Staphylococcus aureus
1 Culture -ve, 1 Haemophilus
influenzae, 1 Staphylococcus
epidermidis
No. of
No. of
injections endophthalmitis
(incidence)
Isolated organism
1833
6 (0.33%)
4 Coagulase -ve S aureus,
1 S aureus, 1 Streptococcus
pneumoniae
600
2 (0.33%)
2 Serratia marcescens
0
0
-
0
0
-
3501
1 (0.028%)
1 Culture -ve
Jonas et al
0
0
-
1218
1 (0.082%)
1 Culture -ve
Velpandian et al21
0
0
-
1000
1 (0.1%)
N/A*
0
0
-
5508
4 (0.07%)
N/A
1184
0
-
0
Pilli et al19
20
CATT Research Group
6
Present study
0
-
* N/A denotes not available
as Streptococcus. Meta-analysis of endophthalmitis
after intravitreal anti-VEGF injections reported the
risk of Streptococcus-associated cases was 3 times
more frequent than after intra-ocular surgery.23 While
the most common microbial sources in postsurgical
endophthalmitis were believed to originate from
the patient’s conjunctiva,39,40 Streptococcus species
were not commonly identified in cultured isolates
from conjunctival flora in patients undergoing
intravitreal injections.41 Haemophilus influenzae
endophthalmitis was reported by Artunay et al25
following intravitreal bevacizumab injections from
a shared single vial. Although insufficient evidence
supports the protective effect of wearing masks
to avoid endophthalmitis, this practice may have
prevented contamination by aerosolised bacteria.
stability and sterility of compounded bevacizumab
stored at 4°C for 15 days and up to 6 months,42,43
avoidance of overnight storage may have greatly
reduced the microbial burden risk within vials,
especially as the manufactured bevacizumab was
preservative-free.
We routinely prescribed moxifloxacin eye
drops to patients after injection. A recent antibiotic
susceptibility pattern study among conjunctival
isolates from patients undergoing intravitreal
injection found most organisms to be sensitive to
gentamicin (≥85%).41 Nonetheless, the protective
role of post-injection antibiotics is controversial.
Prospective controlled trials found that the omission
of peri-injection antibiotics did not increase the rate
of endophthalmitis.44-46 Some concern exists about
No scientific data have revealed how best the possibility of microbial resistance with repeated
to divide the large bevacizumab volume in each short-term topical antibiotic use.47
vial into smaller units so as to minimise the risk of
The one case of rhegmatogenous retinal
endophthalmitis. To date, the reported frequency
detachment in this series may or may not be related
of drug preparation–related endophthalmitis was
to the intravitreal injection, as it can develop as part
higher when it was compounded into aliquots
of the natural history of highly myopic eyes. No
as opposed to drawing multiple doses out of
adverse systemic events occurred during the study
the original vial immediately before consecutive
period. Nonetheless, complications after intravitreal
6,16,17,19-21,25
injections (Table 4
). A possible reason might
anti-VEGF injections in this study could have been
be that accredited compounding facilities were not
under-recognised owing to retrospective collection
available in many localities and compliance with the
of some of the data.
16
standards of sterile compounding were poor. In our
protocol moreover, the opened bevacizumab vials For intravitreal injections, ranibizumab costs
were not stored overnight, which was also practised approximately US$2000 per dose while bevacizumab
for Lee et al’s cohort16 in which no cases of infective costs approximately US$50 to US$100 per dose.
endophthalmitis were encountered. The revised USP Since treatment with both drugs entails multiple
(chapter 797) incorporated microbial contamination doses, the cost differential is substantial. In the CATT
into the determination of beyond-use dating, quite study, the average 1-year costs for regular monthly
apart from the chemical stability of the products.30 treatment with ranibizumab and bevacizumab
Although previous studies have demonstrated the were US$23 400 and US$595, respectively.48 Because
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493
# Ng et al #
they are less costly, in the treatment of neovascular
AMD, intravitreal injections of bevacizumab will
increase in popularity with the availability of level I
evidence on their efficacy and safety in comparison
to ranibizumab.6 Many practices in both developed
and developing countries have no alternative but to
prepare small aliquots for intra-ocular injections in
their own facilities before its use is licensed.21 Jonas
et al20 reported that the risk of endophthalmitis could
increase by 0.1% for every injection of bevacizumab.
As endophthalmitis is a rare complication following
intravitreal injection, it is difficult to arrive at any
statistical conclusion regarding a comparison
between bevacizumab and ranibizumab. However,
this retrospective study spanning 4.5 years is already
of reasonable duration. The theoretical increased risk
of endophthalmitis associated with the additional
procedures in fractionating the large bevacizumab
vial for ‘off-label’ ophthalmic indications should
not be neglected. Currently, there is no consensus
regarding the preparation of bevacizumab into small
doses for ophthalmic indications, and prospective
study with a large sample size and long followup duration is needed to investigate the optimal
protocol to minimise the risk of contamination. For
this purpose, many centres aliquot multiple syringes
from a single vial to be kept in a refrigerator for use.
However, this study showed that there were no cases
of endophthalmitis after the same vial was reused for
a maximum of 10 consecutive injections, overnight
storage of opened vials was avoided, and wearing
surgical masks during intravitreal injections was
mandated.
Disclaimer
None of the authors had relevant financial
relationships to disclose regarding this study.
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